Neutrophils (PMNs) provide the first line of host defense against bacterial periodontal infections. How and why PMNs fail to prevent this infection in adult periodontitis is currently unknown. It is clear that biological mediators which modulate the PMN response, initially interact with receptors, secondarily activate biochemical responses, and finally activate cellular responses. We therefore reasoned that toxic bacterial products may use similar mechanisms to alter PMN function. Short chain fatty acids (SCFAs) are particularly interesting in this regard because they: are metabolic by-products of periodontal pathogens; are found in gingival crevicular fluid of adult periodontitis patients in mM concentrations; trigger some secondary messengers (e.g.: cytoplasmic calcium, pH, and actin transients); but, inhibit chemotactic receptor mediated PMN functions. However, the mechanism of this action is unknown. This leads us to ask two related questions: 1) How do SCFAs trigger second messengers? and 2) How do SCFAs inhibit normal chemotactic receptor mediated function? To answer these questions we will study the in vitro and in vivo effects of SCFAs + chemotactic mediators on key steps in the signal transduction pathway and key cellular responses. Signal transduction experiments will examine receptor modulation, G-protein activation, and cytoplasmic calcium, pH, and actin transients. Cellular response experiments will examine cell polarization, actin localization, and oxygen metabolism. We will utilize four SCFAs which exhibit the highest gingival crevicular fluid concentration in periodontal disease (acetate, propionate, butyrate, and lactate). Previous work indicates that propionate and butyrate inhibit PMN function, while acetate and lactate do not. We will also examine the effect of caproate, a SCFA not associated with periodontal disease, and combinations of all the indicated SCFAS. These studies are significant for two reasons. First, they offer the potential for providing both a chemical and cellular explanation as to why PMNs fail to prevent periodontal infections. Second, they will characterize the effects of simple organic molecules on PMN signal transduction and cell function. Clearly, this information can be applied to the study of signal transduction and cell function in other cell systems (eg: epithelial barrier function and cytokine production). Finally, this information will potentially provide data which can be used to prevent periodontal pathogenesis.